Linking LEDGF/p75 Overexpression With Microsatellite Instability and KRAS Mutations: A Small-Scale Study in Colorectal Cancer.

Abstract

Introduction: Colorectal cancer (CRC) ranks third in men and second in women, with 153,020 new cases and 52,550 deaths in 2023, and with a projected incidence of 2.2 million new cases by 2030 due to lifestyle changes and enhanced diagnostic capabilities. Identification and analysis of new biomarkers, like lens epithelium-derived growth factor splice variant of 75 kDa (LEDGF/p75), which is known to play a crucial role as stress-related oncogene, can make a significant contribution in facilitating early CRC detection.

Methods: This study analyzed the expression of LEDGF/p75 and the ubiquitin E2 conjugating enzyme UBC13 in 15 CRC tissue samples and adjacent non-tumor tissues. All patient samples underwent NGS-based mutation analysis beforehand. The western blot technique was used for protein analysis, and the results were further validated using mRNA expression data from 521 patient samples from the TCGA database.

Results: LEDGF/p75 expression was significantly elevated in nearly all tumor tissue samples compared to adjacent tissue (11/15, 73.3%). Additionally, the UBC13 enzyme, a key regulator in the degradation of signaling molecules, was also increased in most tumor tissue samples (9/15, 60.0%). Co-overexpression of LEDGF/p75 and UBC13 was evident in 6/6 patients. Patients with KRAS and MSH2 mutations showed a 75% and 100% correlation with LEDGF/p75 overexpression, respectively.

Conclusion: This study confirms the upregulation of LEDGF/p75 in CRC and shows its correlation with KRAS and MSH2 mutations. The interaction of LEDGF/p75 with DNA damage response proteins may contribute to drug resistance and increased tumor aggressiveness. LEDGF/p75's potential as a prognostic biomarker independent of lymph node involvement or CEA levels highlights its potential in personalized therapy, and warrants further research into its therapeutic targeting.